The proposed research is designed to determine the role of the thymus in the recognition of self versus nonself major histocompatibility antigens, as expressed on the thymic epithelial cells, by T lymphocytes. The importance of this process in T cell tolerance to self antigens and the ability of T cells to collaborate with other cells in the generation of immune responses involving more than one cell type will be determined. Using congenitally thymus-deficient (nude) mice implanted with allogeneic thymus glands as the basic experimental system, with nonimplanted nudes and syngeneic thymus-implanted nudes as controls, four basic questions will be addressed. 1) Using skin allografts, mixed lymphocyte reaction tests and 51Cr release assays, the specific reactivity of T cells which have matured under the influence of allogeneic thymi towards the H-2 antigens of the thymus-donor, the nude-host and unrelated, third party strains will be determined. 2) Thymus-donor strain-specific immunosuppressive cells and/or factors will be identified by transfer to newborn or irradiated adult BALB/c mice subsequently grafted with thymus-donor strain skin or by transfer to BALB/c cell cultures responding to thymus-donor strain stimulator cells in MLR and 51Cr release assays. 3) The ability of T cells which have differentiated within allogeneic thymi to respond to foreign antigen in association with thymus-donor, nude-host or third party, unrelated H-2 antigens will be investigated by studying the ability of T cells from allogeneic thymus-grafted nudes to develop into TNP-specific cytolytic effector cells following stimulation in vitro with TNP-modified stimulator cells. 4) The ability of T cells which have differentiated within allogeneic thymi to function as T-helper cells with macrophage and B cells from thymus-donor and/or nude-host strains will be studied in vitro by mixing T cells from nudes given allogeneic thymi with sheep red blood cells and macrophage plus B cells from thymus-donor or nude-host strains in Marbrook tissue culture chambers and subsequently assaying for sheep red blood cell-specific plaque-forming cells.